The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 ± 6 [saline] vs. 319 ± 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 ± 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 ± 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3. T he hypothalamic melanocortin system is a regulator of energy homeostasis. The agouti-related protein (AGRP), produced in the arcuate nucleus, is an antagonist at the melanocortin 3 and 4 receptors (MC3-R and MC4-R), which are distributed throughout the brain. The proopiomelanocortin (POMC) products, such as ␣-melanocyte-stimulating hormone (␣-MSH), act as agonists at the melanocortin receptors (1-3). Hypothalamic POMC mRNA, AGRP mRNA, and the density of MC4-R have been shown to be altered with nutritional status (4,5). Defects of POMC processing and mutations of MC4-R in humans and mice are associated with gross obesity (6-11).5Administration of the synthetic MC3/4-R agonist MT II into the forebrain ventricles or directly into the paraventricular nucleus (PVN) of the hypothalamus of rats or mice produced a dosage-dependent reduction in food intake and body weight (12)(13)(14). A single injection of either the endogenous (AGRP ) or the synthetic (SHU9119 and HS014) MC3/4-R antagonists stimulated food intake in rodents (12,13,15,16). Chronic administration of the more selective MC4-R antagonist, HS028, for 7 days via an osmotic minipump significantly increased food intake and body weight. Tachyphylaxis to HS028 did not occur. However, neither energy expenditure nor pituitary function were examined in this study (17). Previous results from this department have demonstrated that AGRP (83-132), the endogenous hypothalamic melanocortin receptor antagonist, significantly increased 24-h food intake and antagonized the anorectic effects of ␣-MSH (16).The melanocortin system also influences energy expenditure. Intracerebroventricular (ICV) administra...
Substantial evidence suggests that impairment of the hypothalamus?pituitary system can occur following an aneurysmal subarachnoid hemorrhage (aSAH). Given that the diurnal cortisol rhythm is primarily controlled by the hypothalamus?pituitary system, this study examined whether changes in diurnal cortisol rhythm occurred after aSAH. Cortisol concentrations were measured in the saliva samples collected from patients after aSAH and other types of cerebral hemorrhage (non-aSAH) in the post-awakening period and at night (21:00?h), and the cortisol awakening response (CAR) and diurnal cortisol decline were determined. The area under the cortisol curve from immediately after to 45?min after awakening (CARauc) in the aSAH patient group was comparable to that in the non-aSAH or healthy control groups. However, an obvious cortisol peak was not found after the awakening period, and the morning/nighttime cortisol ratio in the aSAH patient group was significantly lower than that in other examined groups due to higher nighttime cortisol concentrations. In aSAH patients, the CARauc and nighttime cortisol concentrations were negatively correlated with the Fisher CT grade. These results indicate that the diurnal cortisol rhythm is not regulated normally after aSAH, and cortisol secretory activity decreases as the volume of subarachnoid bleeding increases. Our findings will be helpful to understand altered hypothalamus?pituitary?adrenal axis function after aSAH.
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